Vasoconstrictor compounds of saccharin and pharmaceutical compositions produced therefrom



Patented Jan. 16, 1951 UNITED smrss VASGCONSTRICTOB COMPOUNDS OF SAC- .CHARIN AND PHAEMACEUTICAL COMBO- SITIONS PRODUCED THEREFRQM William F. Hamilton, Altaden'a, Calif.

No Drawing. Application-October '18, 19.48,

Serial No. 55,236

drug w'hich'will give the patient immediate relief by shrinking congested nasal mucosa, and which will at the same time have a marked correcti-ve eiie'c't against the bacterial invaders which cause the congestion, as well ascrovide re lief from neuralgia headaches by mild local anesthetic action. The'N salts of saccharin with vasocon'stri'ctive amines, according to this'invention,iully'meet these requirements.

Itis a further'objectof-this invention to provide a pharmaceutical which may he used small amounts and low -.concentrations=and still achieve the desiredt'h'erapeutic effects. This ob ject is attained by my new salts, whose formation is evidenced by physiological synergism which is apparent clinically as well as .bacteriologically.

,-A further-object of the invention'i's'toprovide a single drug which is readily retained by the .mucosa in intranasal therapy, which exerts 'a prolonged compound therapeutic eiie'ct locally,

.and which is notlimmediately or relatively soon eliminated by nasal discharge or secretions. Apparently, most nasal medication is soon eliminate'd from the nasal mucosa by the body fluids, and it is, therefore, anlobject of this invention to provide a drug which will be gradually eliminatedover a pericdofsix to twelve hours or more.

Another object of this invention is to provide 'a s'table, clear therapeutic solution which may be sterilized :by" heat and which will keep indefinitely when stored. under normal atmospheric coni'ditions, without harmful deterioration or color Ichange. a

It isa further object of .this invention .to provide compounds which are relatively nontoxic,

and which maybe used topically as vasoeonstric tive local anesthetic antiseptics.

Anotherobject of this invention is to provide drugs'for nasal or oraladministration which are pleasing :to :the taste, andas even .a small amount of free saccharin in solution has a sickeningly sweet taste to many persons, it was necessary to formulate therapeutic solutions seas to incdify or substantiallyeliminate undesirable sweetness.

A further object of this invention is to provide a mew series \of salts of the vasoconstrictive NT OFFICE 2 amines which potentiates the desirable vasjo'constriotive eifects of theamines and reduces the undesirable side reactions of the drugs, such as tachycardia, nervousness, sleeplessness and the like.

Ideally, nasal medicaments should be aqueous, isotonic or slightly hypertonic solutions which give rapid and prolonged :vasoconstriction without untoward side effects, which are not irritating to the mucosa and which are relatively nontoxic systemically, which correct the bacterial fiora of the upper respiratory tract *by bacterici- 'dal or "bacteriostatic action, and which provide relief from pain and -headaches 'by"promoting natural drainage and'reducing'congestion as well as'by a'mildlocal-anesthetic effect. lt is, therefore, an additional object of this invention to provide such aqueous solutions, and to provide the active drugs which-causesucheffects.

Most medicaments are unfortunately unpieasant for patients to take, and may cause nausea, vomiting or other undesirablereactions in individual case's. Consequently, it is another object of this invention to provide medicaments which may be dispensed in several iflavors and which will {thus .cbe available to *meet the individual tastes of sensitive ipatients, without-changing the beneficial effects :01" the active drugs.

lIliese and other objects and ifeatnres of the invention will become apparent from the following detailed description of this invention.

In connection with my discovery .ofithe Nesalts of 'saccharin with salt-forming 'vasooonstrictive amines, I have .not only found them to be highly desirablelfor yielding the above'mentionedefiects of vasoconstriction, antibacterial activity and local anesthesia, and for providing the desirable feature of' accomplishing the qnecessary therapeutic effects (with low concentrations and for :relatively prolonged periods'of tiinabut 1 have also found that they produce such results without objectionable effects as above indicated.

Saccharin itself, i. e., o-sulfobenzimide, {is a stable, nontoxic .acid of moderate strength which has been used as a sweetening agent for many years since its discovery in 1879 by- Remsen and Fahlberg. There is apparently nocase onir'ecord where human illness hasTbeen ascribed totheujse of saccharin in normal amounts. In aqueous 'media, saccharin forms N-salts with alkalinematerials. Thus: w

' (Saccharin) (Sodium saccharin) Because the :sodium salt of saccharin is vet-y soluble in water and because sacchariniitself not very soluble, this salt is Organic Chemistry of Sulfur, Suter, John Wiley & Sons Inc., N. Y., 1943).

ties, the only commercially useful salts, aside from the sodium salt, of which I am aware are Of the many possibilithose formed with the phenylmercuric ions (UQS.

Patents 2,087,959 and 2,135,533) which are antiseptics.

By the term saccharin I mean to include both o-suliobenzimide and its relatively nontoxic, water-solubie derivatives which still contain the typical heterocyclic nucleus By the term vasoconstri-ctive amines" I mean to include all those amines which have a local vasoconstrictive effect and which are related to phenyl ethylamine, inter alia:

C-phenyl alkylamines such as phenyl ethylamine.

amphetamine (benzedrin-e) which'is l-phenyl-2-amino propane; and desoxyephedrine which is 1=phenyl-2-methylamino propane;

C-phenyl alkylolamines such as ephedrine which is l-phenyl-Z-rnethylamino propanol-l, and norephedrine (propadrine) which is l-phenyl-Z-amino propancl-l; I V C-hydroxyphenyl alkylamines such as tyramine which is p-hydroxyphenyl ethylamine, paredrine which is ,B-aminopropyleiehydroxybenzone, and kephrin which is l-(SA dihydroxy phenyl) -2methylamino ethanone-l;

C-hydroxyphenyl alkylolamines such as neocyclohexyl amine; and in addition the N-saltforming nitrogen heterocyclic privine which is 2-(1-naphthylmethyl) -imidazoline, and which also possesses the same vasoconstrictive characteristics. In other words, the term vasoconstrictive amines is intended to embrace sympathomimetic or pressor drugs having salt forming amine groups and pronounced local vasoconstrictive action, as is well understood pharmacologically, and having therapeutic value, at least when combined as constituents inthe new compounds of this invention. Sther amines inthose 4 cluded are substances such as: epinine, hordenine, mescaline, arterenol, p-aredrinol, suprifen and veritol.

I have discovered that any vasoconstrictive amine having a salt-forming amine group will react with saccharin to form a complex N-salt in which the imido nitrogen is trivalent and the amino nitrogen is pentavalent. The pharmacodynamic grouping characteristic of all of these 7 compounds is and as long as this linkage is maintained the compounds have a high degree of physiological activity. It is also to be noted that the N-saccharin salts given herein as having physiological activity, have in the amine radical at least four carbon atoms of which at least three are in a series carbon to carbon linkage attached at one end to the amino nitrogen.

The salts of saccharin or this invention may be prepared by the simple addition of equimolar quantities of saccharin to the amine, at room temperature, when the amine is liquid; by mixing equimolar quantities of saccharin sodium and the acid' salt of the amine with water to form an aqueous solution which contains the amine salt of saccharin and the sodium salt of the acid from the amine; or by mixing equimolar proportions of the amine and saccharin in water, or some other suitable solvent. Other temperatures than room temperature may be employed up to about C. in most cases, since the agents used are in most cases stable to at least 1G0 C.

In the present invention, the structure of the compounds is well indicated by the salt desoxyephedronium o-sulfobenz'imide:

which, being the substituted ammonium salt 'formed between the acidic saccharin and the ephedrine and saccharin may be indicated conventionally:

and the meaning of this formula is identical to and merely clarifies the structure outlined in the preceding paragraph. V

The salts formed between saccharin and the vasoconstrictive amines are new compositions of matter. They have new and different properties as compared with the reactants themselves. In general, they are very soluble in water in comparison with the sparing solubility of saccharin or the amine. In general, the amines are limpid liquids or solids and-the saccliarin a crystalline solid, whereas the salts are viscous liquids,

crystals or transparent gums or resins depending upon the amine used in the reaction. pH titration curves between the amines'and the saccharin indicate that at equimolar proportions the end point of the reaction is reached, and the pll of a the salt formed is eitherapproximately neutral or Clear area I Compound tested, 10% aqueous -Soluti Diameter Oll- Sodium Saccharin Ammonium Saccharim.

2-an'rino heptanc sulfate. Desoxyephedrine hydrochl 2-heptylammoniuli1 saccharin Desoxyephedronium saccliarin It is readily seen that in these tests neither sodium saccharin, ammonium saccharin,"desoxyephedrine l iydrochloride, or 2- aminoheptane-'sul 6* 7 various -"sacc harin amine salts and mixtures in tube cultures .Saccharin salt offgg gg -.Girewth1.l-nhibition Per cent 1 .Good. Desoxyephedrine 0.5 Nil.

' 0.1 "'Do. -1 Good. Z-Aminoheptane 0. Poor.

0.1 Nil.

1 Good, not complete. Cyclohexyl amine 0. 5 Med.

0.1 Poor. 1 Good. Desoxyephedrine, Sodium .Lauryl 0.5 Do.

sulfate, 1:35 0. 1 Excellent.

. 0.105 Approx. 50%. 1 Excellent. 2-am1nol1eptenewith Sodium Lauryl 0.5 Very good.

sulfate, 1:35 0.1 Excellent.

I 0. g5 go. T 0. o. l\selcisfyzliggpli rgl5ne with Sodium Lauryl O 1 Excellent l00;%

' 0.05 Approx. 30%.

fate had any marked inhibitoryei'fect on the growth or" S. dureas, whereas under identicalconditions the salt of desoxyephedrine with saccharin was moderately potent against the growth and the salt of Z-aminoheptane and sa'ccharin was very potent in its ,growthjnhibition. This synergism is due to the chemical compound formation between the amineand the saccharin.

A;-number of saccharin-amine salts were prepared andtested-on agar plates under identical conditions, andthe results below indicate that the above conclusion iszalgeneralityz Compound oi Saccharin-tvith- Clear Hazy Percent Phenylethyl amine. Phenylisopropyl amine Ephedrine.

aint

n-Heptyl amine Di-n-Heptyl amine n-octyl amine Decyl amine Dodecyl amine. Benzyl amine Oycloheryl amine. Pyridine Octadecyl amine Emulsified, could not test.

While the growth antagonism tests on agar plates are indicative of activity, they-are not "in themselves sufficient'to base complete conclusions upon. Therefore, several seriesof tube cultures were made, in which the nutrient broth in test tubes was inoculated with S. aureus, and the desired concentrations of the materials to be tested were added. Growth after 24 hours incubation was estimated 'bythe cloudiness and amount of sediment in the cultures, and the con centration of the nutrient *broth was in all --cases adjusted to insure strictly comparable results.

The following tabulation indicates the e'fiec't of Soln decomposed.

than they are on the agar plates, and that in relatively small amounts they have pronounced growth antagonism characteristics.

For clinical use, because of the pronounced vasoconstrictive properties of the salts, they can not be used in higher concentrations :in nasal medicaments than approximately 0.5% without causing-too much vasoconstriction 'i-n'the nose, and the untoward-effect of blanching the nasal mucosa. Therefore, it was necessary to add to the salts .an ingredient increasing the antibacterial growth characteristic, and it was found that sodium 'lauryl sulfate, a wetting agent, would achieve this result in an unpredictable "fashion. For example, inagarplatetests, sodium lauryl sulfate-at 0.06%-o0noentration gave a clear ring-of inhibition-of 15 mm. diameter; desoxyephedrine saccharin salt in 10% gave 16.5 mm. whereas the two together gave 23 .mm. In contrast, sodium lauryl sulfate had no effect on the size of the inhibited areas-of either Z-aminoheptane er cyclohexyl amine saccharin salts. Again, the salt of neosynephr ine saccharin had little *pla-te aOtivity, butwiththe Wetting agent tube cultures it exhibits marked bactericidal activity in concentrations .as low as 0.05%. :In 0.10% solutions which showed excellent growth inhibition, no-S. aureusgrew-in either culture orstreak tests of liquid removed from the solution showing that the salt was actually bactericidal and the ba'cteria-had'been killed, whereas similar cultures from either' the 'Z-aminoheptane or desoxyephedrinesolutions showed growth-and thesetwo salts were therefore bacteriostatic in their action.

In aqueous solutions the saccharin -amine salts hydrolyze to-give'some free saccharin and amine.

air and sunlight and .pr'efcerably warmed at the same time, the sweet taste becomes so diminished as to be either hardly noticeable, r acceptable even to those sensitive to sweets. What happens might be expressed by the following equations, using the desoxyephedrine salt as an example:

(Molecular complex, desoxyephedrine-o-sulfamido benzoate) Although I do not Wish to be bound by this explanation, the free saccharin formed by hynontoxic neutral salts may be used in appropriate proportions, such as magnesium chloride,

potassium chloride, calcium chloride, sodium bicarbonate and sodium dihydrogen phosphate.

The following examples illustrate more specifically the nature of my invention:

Example I The salt of saccharin with desoxyephedrine was prepared by mixing equimolar proportions of the two ingredients, stirring gently until all of the solid saccharin had disappeared. Thus, 1.831

drolysis of the amine salt hydrolyzes in the presence of light and air and is removed from the solution, being converted to o-sulfamidobenzoic acid. This acid then reacts with the free amine in solution to form a molecular complex of the indicated structure. The complex hydrolyzes reversibly to give the free amine and acid again, and by the law of mass action, the free amine shifts the saocharin salt hydrolysis equilibrium and greatly reduces the amount of free saccharin in solution, thus diminishing the sweet taste.

The ferric. salt of o-sulfamidobenzoic acid is quite insoluble in water, but the ferric salt of saccharin is soluble, and no precipitation occurs when ferric chloride is added to desoxyephedrine hydrochloride. When ferric chloride is added to a freshly made solution of desoxyephedronium saccharin, no precipitate forms at first, but if the solution has been exposed to light and air, a precipitate is formed. This indicates that o-sulfamidobenzoic acidis formed in the solution, and the fact that the solution does not lose its clinical or antibacterial properties after ageing many months indicates that the reaction is slowed tremendously by the presence of excess amine ions.

The sweet taste of the saccharin-amine salts may be further camouflaged by the addition of flavors, such as menthol, lemon, clove or cinnamon. Gare must be used in the selection of the flavor or the sweet taste may be accentuated. Because the solutions should be isotonic or slightly hypertonic for use as nasal medicaments, it is necessary to add an inert salt or bufier'to the solutions. Sodium chloride may be used for this purpose, but magnesium sulfate has been found preferable because of its bitterness, which effectively offsets the mild residual sweetness characteristic of the 'imide-amine compounds. In addition to the mentioned neutral salts, sodium chloride and magnesium sulfate, other water soluble parts of saccharin and 1.491 parts of desoxyephedrine (by weight) were stirred together. As the saccharin dissolved, the mass became more and more gummy, and finally. stifi. It does not crystallize, and breaks with a conchoidal fracture.

The gum is water white, readily soluble in water giving an approximately neutral or slightly acid solution, readily soluble in ether, and poorly soluble in benzene. Chilling its concentrated aqueous solution results in the formation of a two phase liquid.

Example 2 Di-n-heptylammonium saccharin was prepared by adding 4.625 parts by weight of saccharin to 5.275 parts by weight of di-n-heptyl amine, and heating gently, stirring'until a clear viscous liquid is obtained. Partial crystallization occurred when the liquid was chilled to 0 C.

The solid is viscous and gummy'at room temperature; it is sparingly soluble in water (approximately 0.5%) it shows Very pronounced vasoconstrictive and local anesthetic effects, particularly on mucous membrane, and effectively inhibits growth of S. aureus.

I Example 3 Ephedronium saccharin H H co SO/ 1m on; on

was prepared as follows: 1.651 parts ofephedrine was'melted with 1.831 parts of saccharin, stirring and heating gently. On cooling the mass became resinousthen gummy, and finally brittle. It did not crystallize, is very soluble in water (over 30%), and is deliquescent.

Example 4 Phenylisopropylammonium saccharin melting point tubes, became a viscous liquid at 9 50-60? C; Thematerial is deliqueseent, rapidly becoming; liquidin themoisture it removes from the air, and does not boil, but decomposes-when heated to:290" C. r

Example 'Iyramine hydrochloride (molecular weight 241.2)

(mole cular weight 173.6)

NaCl 21120 S02 Tyrammo ium saccharin I (molerulzrwcigh't 320.2) To make 0.5 part by weight of the compound:

."/:=0.3'76 part sodium saccharin required.

3 2Q 2 173. 6 p 0. 5 y 11:0.271 part tyramine hydrochloride required. The weighed amounts of sodium saccharin and tyramine. hydrochloride were dissolved in 5 parts of water, and" the resulting solution contained tyrammonium saccharin. 1.8% sodium chloride.

Example 6 Tosprepare the pure salt of? saccharin and: a?

reactants are used, and the reaction goesto com-- pletion.

Example 7 Nasal medication should be isotonic or slightly hypertonic, and clinical tests have demonstrated that an 0.5% solution of desoxyephedronium saccharin gives adequate vasoconstriction, efiec- 'tive? bacteriostasis, and relief I from pressure and neuralgicheadaches. A preferred embodiment of thisinvention in such a solution is prepared asfollows:

To approximately 3 liters of'water, add,,with constant stirring at room temperature, 11.04 grams saccharin. Then, stirring continuously, add". 9.76" ml. desoXyephedri-ne, and: stir for. at

least one-hour until the solution-is entirely clear.

Then. add and'dissolve 40.0 grams Epsom salts (magnesium sulfate heptanydrate), 1.00 gram Duponol C sodium lauryl sulfate with 40% sodium sulfate), 4.0 ml. lemon extract (lemon dissolved in ethano1),.0.020 gram mentho1,.and 2' ml. anise extract. Then add water, (1'. s. 4liters;

The resultant cloudy solution is allowed, to standseveral'days in strong, light, and is then fine filtered and bottled in suitable container. The pH of the solution is 5.5-7.0; it'is mildly sweet andrhas a pleasantmild'licoricetaste; will almost completely"inhibitithe" growthv of S. aarea's even ata 5:111 dilution, permits' ciliaryactivity to continue: for-reasonable period of time, is relatively nontoxic systemically. and inclinical? tests" on over one hundredfpatients it has not caused complaints of sleeplessness, nervousness, tachycardia, or other untoward sideeilect's. but it has given outstanding symptomaticrelieffrom pressure and neuralgia headaches; The solution. is." administeredby-jetting 015-02 ml. highinto the nose, using'2-3 jets in eachnostrilevery 2-3 hours;

Example 8.

Solid, crystalline salt of neosynephrine-Saccharinis preparedby dissolving 3.492 parts of neosynephrin'e hydrochloride and 3.756 parts of sodium saccharin (commercial-salt-' containing 5 moisture) in'l'llilfiparts' of absolute methanolby volume. After stirring-until the solution is clear, 4-00- parts by. volume'ofdiethy-lether are added. The stcichiom etric amount of precipitated sodium chloride isfiltered from :the-reaction mixture, and the filtrate is'vacuum' evaporatedat room tem-:- perature untilthe'mass'is gummyand there is noresidual odor of methanol. Then, 25' parts of benzene is added, and: the mixture is'allowed to stand overnight. at room temperature, after which the benzeneand traces'of ether, methonal, and moisture are removed by evaporation under h gh vacuum (0.3- micron of mercury or better). Thecolorless gum and'white solid residue gradually crystallize after standing severalweeks'at room temnerature. The crystals which form are very soluble in water, and-'melt sharply at about 103 C., and may be: identified chemically as a-hydroxy-c-methylammoniumethyl -3-hydroxybenzene-N-o-sulfobenzimide.

" Example 9' Crystalline n-hexyla-mmonium-N-o-sulfobenzimide is prepared by purification by distilling commercial n hexylamine and collecting that fraction condensed from the vapor when the ;tem+

.perature is between 128 C. and 128.5 C. andm xing 10.12 parts'by weight of'the -distillate with 18.31 parts by weight of saccharin. The mass grows warm as heatis evolved by the reaction,- and is-stirrcduntil it' becomes a' clear, water White, viscous liquid. It is then transferred to. a dry, tightly capped. container and stored at sub-freeztemperatures until crystallization commences. Aitercrystals start t'o form; the containerwis stored at room temperature for several months until the entire mass has crystallized.

The n-hexylammonium-N-o-sulfobnzimide is a white, waxy or unctuous, crystalline solid which resembles paraifin wax, and which is deliquescent. It melts at 35 C. to 40 C. to form a clear, water white, viscous liquid.

Example A preferred therapeutic solution of the salt of neosynephrine saccharin may be prepared as follows: In about 3 liters of water, dissolve, with Water, q.s. 4 liters.

The clear solution is filtered and bottled in suitable amber glass containers and is ready for use as nasal medication. The sodium chloride renders the solution isotonic, or slightly hypertonic, as would ordinarily be true of other solutions hereof as is well understood in this art.

This medication is very mildly lemon flavored, is salty and very slightly sweet to the taste, and has been found pleasing and effective by a very large number of patients. It gives adequate and prolonged vas'oconstriction, relief from neuralgic and pressure headaches, and is well tolerated in doses of 2-5 ml. per day as required. It is bactericidal against Stqphylococcus am'eus, Streptococcus hemolyticus and Streptococcus viridans.

I Freedom from side effects has been outstanding.

The concentration of the active drug, which is a-hydroxy-,B-methylammoniumethvl -3-hydroxybenzenel l-o-sulfobenzimide is 0.15

The foregoing examples are merely illustrative of suitable methods for preparing representative salts of saccharin with vasoconstrictors having a salt forming amine group, and pharmaceutical compositions embodying these salts for use as nasal medicaments. They are not intended to limit the scope of the invention, or preparations for other medicinal uses.

While the salts are in general soluble in water, some of the salts prepared from amines derived from the higher fatty acids are sparingly soluble, and my experiments indicate that they may find application for use as emulsifying agents, detergent compositions, topical application as simultaneous local anesthetics, vasoconstrictors, bacterial growth inhibitors, and the like.

I claim as my invention:

1. As a new chemical compound, an N-salt of saccharin and a vasoconstrictor amine in which the amine has at least four carbon atoms of which at least three are in a series carbon to carbon linkage attached at one end to the amino nitrogen.

2. As a new chemical compound, an N-salt of saccharin and a vasoconstrictor amine selected from the group consisting of C-phenyl alkylamines, C-phenyl alkylolamines, C-hydroxyphenyl alkylamines, C-hydroxyphenyl alkylolamines, alkylamines in which the amine has at least four carbon atoms of which at least three are in a series carbon to carbon linkage attached at one end to the amino nitrogen, and 2-(l-naphthylmethyl) -imidazoline.

3. As a new chemical compound, an N-salt of saccharin and a vasoconstrictor alkylamine in which the amine has at least four carbon atoms of which at least three are in a series carbon to carbon linkage attached at one end to the amino nitrogen. 7

4. As a new chemical compound, an N-salt of saccharin and a vasoconstrictor C-phenyl alkylamine. a

5. As a new chemical compound, an lN-salt of saccharin and a vasoconstrictor C-phenyl alkylolamine.

6. As a new chemical compound, an N-salt of saccharin and a vasoconstrictor C-hydroxyphenyl alkylamine.

'7. As a new chemical compound, an N-salt of saccharin and a vasoconstrictor C-hydroxyphenyl alkylolamine.

8. As a new chemical compound, an N-sacoharin salt of l-phenyl-Z-methylarnino propane.

9. As a new chemical compound, an N-saccharin salt of dodecylamine.

10. As a new chemical compound, an N-saccharin salt of a-hyclroxy ;cmethylamino ethyl-3- hydroxy benzene.

11. As a new chemical compound, an N-saccharin salt of 1-phenyl-2-amino propane.

12. As a new chemical compound, an N-saccharin salt of l-phenyl-2-methylamino propanol-l.

' 13. A pharmaceutical preparation comprising, an aqueous solution of anN-salt of saccharin and a vasoconstrictor amine in which the amine has at least four carbon atoms of which at least three are in a series carbon to carbon linkage attached at one end to the amino nitrogen.

1 1. A pharmaceutical preparation as defined in claim 13 in which sodium chloride is also present in said solution.

15. A pharmaceutical preparation as defined in claim 14 which also contains a cationic wetting agent having a dodecyl carbon chain in said solution. I

16. A pharmaceutical preparation which comprises, an aqueous solution of the N-salt of saccharin and 1-phenyl-2-methylamino propane, said solution also containing sodium chloride and a cationic wetting agent having a dodecyl carbon chain.

WILLIAM F. HAMILTON.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,408,345 Shelton Sept. 24, 1946 FOREIGN PATENTS Number Country Date 12,181 Great Britain 1902 25,151 Great Britain 1899 OTHER REFERENCES Barger: Journal of Physiology, vol. 41, pages 19-28, Oct. 18, 1910.

Chem. Abstracts, vol. 29 (1935), pages, 3996- 3997, citing Mameli, Gazz. Chim. Ita1., vol. 65, pages 51, 66.

Physiological Reviews April 1946, pages 191.

Wood-Osol: United States Dispensatory, 23rd ed., 1943, page 130. 

1. AS A NEW CHEMICAL COMPOUND, AN N-SALT OF SACCHARIN AND A VASOCONSTRICTOR AMINE IN WHICH THE AMINE HAS AT LEAST FOUR CARBON ATOMS OF WHICH AT LEAST THREE ARE IN A SERIES CARBON TO CARBON LINKAGE ATTACHED AT ONE END TO THE AMINO NITROGEN. 